The molecular basis of a heavy chain disease-like gamma 2b immunoglobulin protein is being investigated. The deletion of a portion but not all of the first domain of the constant region is a consequence of an RNA splicing alteration. The genomic DNA encoding the mutant RNA has been cloned into a bacteriophage vector and currently is being sequenced. Subtle DNA changes at or near splice junctions are probably responsible for the altered splicing pattern and the alterations in mRNA metabolism. These studies may elucidate the signals important for RNA splicing and a mechanism by which heavy chain disease may arise. The extent of the deletion of the mRNA is being determined. The metabolism of the mutant mRNAs is being studied by measurements of the rates of synthesis and degradation. The influence of the splicing alteration on the downstream splicing of the 3' membrane anchoring exon is being studied. Mutants which have switched from expression of the gamma 2b constant region gene to the expression of the gamma 2a constant region in association with the same variable region are being investigated. These studies are aimed at understanding gene rearrangements resulting in the switching of immunoglobulin classes during plasma cell development. The mutant genes are being cloned in bacteriophage vectors and mRNAs analyzed by hybridization and S1 nuclease mapping.